Durability of Original Monovalent mRNA Vaccine Effectiveness Against COVID-19 Omicron–Associated Hospitalization in Children and Adolescents — United States, 2021–2023

Pediatric COVID-19 vaccination is effective in preventing COVID-19-related hospitalization, but duration of protection of the original monovalent vaccine during SARS-CoV-2 Omicron predominance merits evaluation, particularly given low coverage with updated COVID-19 vaccines. During December 19, 2021-October 29, 2023, the Overcoming COVID-19 Network evaluated vaccine effectiveness (VE) of ≥2 original monovalent COVID-19 mRNA vaccine doses against COVID-19-related hospitalization and critical illness among U.S. children and adolescents aged 5-18 years, using a case-control design. Too few children and adolescents received bivalent or updated monovalent vaccines to separately evaluate their effectiveness. Most case-patients (persons with a positive SARS-CoV-2 test result) were unvaccinated, despite the high frequency of reported underlying conditions associated with severe COVID-19. VE of the original monovalent vaccine against COVID-19-related hospitalizations was 52% (95% CI = 33%-66%) when the most recent dose was administered <120 days before hospitalization and 19% (95% CI = 2%-32%) if the interval was 120-364 days. VE of the original monovalent vaccine against COVID-19-related hospitalization was 31% (95% CI = 18%-43%) if the last dose was received any time within the previous year. VE against critical COVID-19-related illness, defined as receipt of noninvasive or invasive mechanical ventilation, vasoactive infusions, extracorporeal membrane oxygenation, and illness resulting in death, was 57% (95% CI = 21%-76%) when the most recent dose was received <120 days before hospitalization, 25% (95% CI = -9% to 49%) if it was received 120-364 days before hospitalization, and 38% (95% CI = 15%-55%) if the last dose was received any time within the previous year. VE was similar after excluding children and adolescents with documented immunocompromising conditions. Because of the low frequency of children who received updated COVID-19 vaccines and waning effectiveness of original monovalent doses, these data support CDC recommendations that all children and adolescents receive updated COVID-19 vaccines to protect against severe COVID-19.


Study Participants
VE of ≥2 original monovalent COVID-19 vaccine doses § against COVID-19-related hospitalizations (December 19, † A comprehensive listing of COVID-19 vaccination recommendations from the Advisory Committee on Immunization Practices is available.https://www.cdc.gov/vaccines/hcp/acip-recs/vacc-specific/covid-19.html§ The original monovalent vaccine was administered for all COVID-19 vaccinations until the bivalent formulation was authorized (on September 1, 2022, for third or higher doses for those aged >12 years; October 12, 2022, for third or higher doses for children aged 5-11 years;and April 22, 2023, for first or second doses for all eligible ages).status, or 5) received a positive influenza test result.¶ ¶ Given subsequent findings of low (3%) bivalent vaccination coverage and no reported receipt of updated (2023-2024 formula) monovalent doses, children who received updated formulations were post hoc excluded from VE analyses.

Statistical Analysis and Vaccine Effectiveness Estimation
Bivariate associations between sociodemographic factors and both case or control status and vaccination status among case-and control patients were assessed using chi-square tests for binomial or categorical variables or Wilcoxon rank-sum tests for continuous variables.VE was estimated among all hospitalized patients and among patients without documented immunocompromising conditions*** and calculated as (1 − adjusted odds ratio) × 100% by time between last vaccine dose and hospitalization and by age, † † † using multivariable logistic regression, § § § including hospital site as a repeated effect using generalized estimating equations, and adjusting for the presence of one or more underlying medical condition, age (in years), month and year of hospitalization, U.S. Census Bureau region of hospital, social vulnerability index (SVI; i.e., continuous ranging from 0-1, with higher scores indicating increased vulnerability), and race and ethnicity.SAS software (version 9.4; SAS Institute) was used to conduct all analyses.This activity was reviewed by CDC, deemed not research, and conducted consistent with applicable federal law and CDC policy.¶ ¶ ¶ ¶ ¶ Patients who had an incomplete COVID-19 mRNA vaccination series included those who received only 1 dose of an mRNA primary series or whose last dose was too recent (second dose was completed within 14 days of hospitalization or third or higher dose was received within 7 days of hospitalization).Those excluded because of unverifiable vaccination status include those whose vaccination status could not be verified through source documentation (such as state immunization information systems, electronic medical records, or pediatrician records) or plausible self-report, whereby a parent or caregiver provided the date and location of dose.*** Immunocompromising conditions included active or previous oncologic disorder or nononcologic immunosuppressive disorder (including solid organ transplant, HIV or AIDS, primary immunodeficiency, bone marrow transplant for nononcologic disease, and other disorder requiring treatment that suppresses immune system).† † † Analyses included time since last dose as a multilevel categorical predictor and used the following cutoffs: 14-119 days for second dose or 7-119 days for a third or higher dose, and 120-364 days for all second or higher doses.The interval between receipt of the last dose and hospitalization was calculated as the number of inclusive days between those events.Models examining VE by age were stratified by age group (ages 5-11 years and 12-18 years).§ § § Multivariable models controlled for the presence of at least one underlying medical condition, continuous age in years, month and year of hospital admission, U.S. Census Bureau region, continuous SVI ranging between 0 and 1, and race and ethnicity, categorized as non-Hispanic White, non-Hispanic Black or African American, Hispanic or Latino, and other races, multiple races, or unknown.

Characteristics of Enrolled Population
During December 19, 2021-October 29, 2023, a total of 3,348 patients were enrolled, including 1,551 (46%) casepatients and 1,797 (54%) control patients.****Only 3% of casepatients and of control patients had received bivalent COVID-19 vaccine, and none reported receipt of an updated monovalent dose; therefore, VE for these specific formulations could not be estimated.Case-and control patients were similar in age, sex, hospital U.S. Census Bureau region, † † † † presence of any underlying respiratory condition (e.g., asthma or chronic lung disease), and clinical support received (Table 1).The presence of at least one underlying health condition was more common among case-patients (82%) than among control patients (73%) (p-value <0.001).Critical illness occurred in 294 (19%) case-patients and 322 (18%) control patients (p = 0.43).Patients living in lower SVI areas were more frequently vaccinated (Table 2).

Discussion
During the period of SARS-CoV-2 Omicron predominance, receipt of ≥2 original monovalent COVID-19 vaccine doses was associated with fewer COVID-19-related hospitalizations in children and adolescents aged 5-18 years; however, protection from original vaccines was not sustained over time, necessitating increased coverage with updated vaccines.Most children and adolescents in this analysis who were hospitalized with COVID-19 were unvaccinated, and few had received updated vaccine doses despite a high prevalence of underlying comorbidities associated with more severe disease.Vaccination frequency declined with increasing social vulnerability, highlighting disparities in vaccination coverage comparable with published estimates from at least one other U.S. public health surveillance network (5).This finding might be driven by factors including vaccine hesitancy or barriers to accessing vaccines among more vulnerable populations (5).
VE of original monovalent doses against COVID-19related pediatric hospitalizations was lower than previous VE estimates reported by the Overcoming COVID-19 Network before Omicron emergence (2).However, VE estimates from this report among children and adolescents hospitalized during December 19, 2021-March 19, 2022, were similar to Summary What is already known about this topic?COVID-19 vaccination was shown to be effective against pediatric COVID-19 hospitalization before the emergence of the Omicron variant.
What is added by this report?
During December 19, 2021-October 29, 2023, receipt of ≥2 doses of an original monovalent mRNA COVID-19 vaccine was 52% effective against pediatric COVID-19 hospitalization and 57% effective against critical illness related to COVID-19, when the last dose was received within the 4 months preceding hospitalization, but protection decreased over time.
What are the implications for public health practice?
These findings support existing recommendations that children and adolescents aged 5-18 years remain up to date with COVID-19 vaccination given low vaccination coverage and waning effectiveness over time against COVID-19-related hospitalizations.
previously published VE estimates from this network among children and adolescents hospitalized within the same date range (2).In a separate U.S. study of children and adolescents aged 5-15 years, VE against symptomatic SARS-CoV-2 infections was reported to wane in the months after a second dose, with improved VE observed after receipt of a booster dose (4).Effectiveness of bivalent vaccine formulations against pediatric hospitalizations was not estimable in this investigation; however, two recent studies report that receipt of a bivalent vaccine was associated with higher VE against symptomatic pediatric infections ( 6) and COVID-19-related hospitalizations in immunocompetent adults (7).

Limitations
The findings in this report are subject to at least four limitations.First, SARS-CoV-2 infection-induced immunity was not assessed (8); increased seroprevalence after Omicron BA.1 emergence (9) might have influenced observed VE.Second, limited viral sequencing data prevented consideration of subvariant-attributed immune evasion (10).Third, limited coverage with bivalent vaccines and currently recommended updated monovalent vaccines precluded the estimation of VE of these formulations.Finally, previously healthy children and adolescents accounted for <20% of case-patients, limiting generalizability.

Implications for Public Health Practice
Among approximately 1,500 children and adolescents aged 5-18 years with a COVID-19-related hospitalization, including nearly 300 with critical illness, original monovalent COVID-19 vaccines were associated with fewer hospitalizations, particularly within the first 4 months after vaccination.† This analysis excludes 58 of 1,797 control patients who received a bivalent vaccine dose.§ All monovalent doses received before hospitalization were original monovalent vaccine doses directed against the original SARS-CoV-2 strain.No child or adolescent had received an updated (2023-2024 formula) monovalent vaccine dose, authorized on September 11, 2022, before hospitalization.¶ Binomial or categorical variables were compared using chi-square tests of independence and continuous variables were compared using Wilcoxon rank-sum tests.** One unvaccinated case-patient had sex noted as "other" and was excluded from this comparison.
† † SVI is a scale (range = 0-1), reflecting a composite score of socioeconomic status, household characteristics, racial and ethnic minority status, and housing type and transportation.A lower score indicates lower social vulnerability, whereas a higher score indicates higher social vulnerability, which might predispose a population to worse health outcomes.https://www.atsdr.cdc.gov/placeandhealth/svi§ § https://www2.census.gov/geo/pdfs/maps-data/maps/reference/us_regdiv.pdf¶ ¶ Underlying medical conditions were coded as not present if they were either specifically marked as absent or if they were not noted in the child's medical record.
The reference group for each comparison is defined by those who did not have the listed underlying health condition.*** Immunocompromising conditions included active or previous oncologic disorder or nononcologic immunosuppressive disorder (including solid organ transplant, HIV or AIDS, primary immunodeficiency, bone marrow transplant for nononcologic disease, and other disorder requiring treatment that suppresses the immune system).(5-11 years and 12-18 years).All children who had received any original monovalent dose received their last dose within the previous year before hospitalization (<365 days).† All models controlled for underlying medical condition, continuous age (in years), month and year of hospital admission, U.S. Census Bureau region, continuous social vulnerability index (range = 0-1), and race and ethnicity (categorized as non-Hispanic White, non-Hispanic Black or African-American, Hispanic or Latino, and other, multiple races, or unknown.Hospital site of enrollment was incorporated as a repeated effect.§ This analysis excludes an additional 264 case-patients and 160 control patients who had documented immunocompromising conditions, yielding 1,244 casepatients and 1,579 control patients without any documented immunocompromising condition.¶ Immunocompromising conditions included active or previous oncologic disorder or immunosuppressive disorder (defined as solid organ transplant, HIV or AIDS, primary immunodeficiency, bone marrow transplant for nononcologic disease, or other disorder requiring treatment that suppresses the immune system).** Where models did not converge, subvariant period (BA.1: December 19, 2021-March 19, 2022 and BA.2/BA.4/BA.5/XBB.1.5/XBB.1.6: March 20, 2022-October 29, 2023) was substituted as a covariate in place of month and year of hospital admission.† † Critical illness was defined as illness resulting in noninvasive ventilation, invasive mechanical ventilation, receipt of vasoactive infusions, extracorporeal membrane oxygenation, or death.Both case-patients and control patients were required to have met this definition to be included in this subanalysis.§ § Some estimates are imprecise (where 95% CIs were wider than 50%), which might be due to a relatively small number of persons in each level of vaccination or case status.This imprecision indicates that the actual VE could be substantially different from the point estimate shown, and estimates should therefore be interpreted with caution.Additional data accrual could allow more precise interpretation.
To address low coverage of updated vaccines and waning effectiveness of the original monovalent vaccine, children and adolescents should remain up to date with COVID-19 vaccination, including the current CDC recommendation for all persons aged ≥6 months to receive vaccination with updated (2023-2024) COVID-19 vaccines (1).

TABLE 1 . Characteristics of children and adolescents aged 5-18 years hospitalized with a COVID-19-like illness and a positive SARS-CoV-2 test result (case-patients) or a negative SARS-CoV-2 test result (control patients) -Overcoming COVID-19 Network, 34 pediatric hospitals, 26 states, December 19, 2021-October 29, 2023 Characteristic (no. with known information)
See table footnotes on the next page.

illness † † among patients without documented immunocompromising conditions ¶
Abbreviation: VE = vaccine effectiveness.* All analyses excluded patients who received a bivalent vaccine dose (43 case-patients and 58 control patients).Models examining VE by time since last dose incorporated a three-level categorical predictor variable (unvaccinated, last monovalent dose 7-119 days before hospitalization, and last original monovalent dose 120 -364 days before hospitalization) to obtain VE estimates for each interval range.Models examining VE by age were stratified by age group